Method of using secretin and compositions made therefrom for the treatment of autism and other neurological, behavioral and immunological disorders

ABSTRACT

Secretin and secretin compositions are used for the treatment of autism and other neurological, behavioral and immunological disorders. The method includes administering an effective amount of secretin, such as Secretin-Ferring, to a patient. In one example, 2 clinical units (CU) of Secretin-Ferring was dissolved in a 7.5 ml solution of sodium chloride and was intravenously injected over 1 minute. In another example, secretin was administered transdermally by applying dimethyl sulfoxide (DMSO) to the patients skin and rubbing about 15 CU of Secretin-Ferring into the DMSO. Other methods and compositions for administering the effective amount of secretin include other transdermal carrier substances, such as gels, lotions, or patches; oral carriers, such as tablets, capsules, or lozenges; inhalation through the nose or mouth (e.g., as an aerosol); suppository forms of secretin and secretin compositions; and using acoustic waves to cause the secretin to penetrate the skin.

RELATED APPLICATION

This application is a continuation and claims the benefit of U.S. patentapplication Ser. No. 09/229,208, filed Jan. 13, 1999, now U.S. Pat. No.6,197,746, which claims the benefit of U.S. Provisional ApplicationSerial No. 60/088,575 filed Jun. 9, 1998, fully incorporated herein byreference, and is a continuation-in-part of U.S. patent application Ser.No. 09/080,631 filed May. 19, 1998 and entitled Method For Assisting inDifferential Diagnosis And Treatment of Autistic Syndromes, now U.S.Pat. No. 6,020,310, which itself claims the benefit of United StatesProvisional Patent Application No. 60/047,049, filed May 19, 1997.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for thetreatment of neurological, behavioral and/or immunological disorders andmore particularly, to a new medical use for the natural or synthetichormone secretin in the treatment of autism and other neurological,behavioral and/or immunological disorders.

BACKGROUND OF THE INVENTION

Autism is a disabling neurological disorder that affects thousands ofAmericans and encompasses a number of subtypes, with various putativecauses and few documented ameliorative treatments. The disorders of theautistic spectrum may be present at birth, or may have later onset, forexample, at ages two or three. There are no clear cut biological markersfor autism. Diagnosis of the disorder is made by considering the degreeto which the child matches the behavioral syndrome, which ischaracterized by poor communicative abilities, peculiarities in socialand cognitive capacities, and maladaptive behavioral patterns.

A number of different treatments for autism have been developed. Many ofthe treatments, however, address the symptoms of the disease, ratherthan the causes. For example, therapies ranging from psychoanalysis topsychopharmacology have been employed in the treatment of autism.Although some clinical symptoms may be lessened by these treatments,modest improvement, at best, has been demonstrated in a minor fractionof the cases. Only a small percentage of autistic persons become able tofunction as self-sufficient adults.

Although much controversy exists about the causes and treatments ofautism, a few established biomedical findings have been made. Manyindividuals with autism experience intestinal difficulties, oftenincluding the inability to digest gluten and casein. Abnormalities havealso been found in the metabolism of the neurotransmitter serotonin andin various parameters of immune system functions, for example, elevatedMeasles, Mumps and Rubella. (MMR) titers. Prior to the discovery of thepresent invention, however, no useful links had been made between thesebiomedical findings, nor had any Success treatments been derivedtherefrom, as disclosed in various articles incorporated herein byreference.¹

¹ Priven, J. (1997). The biological basis of autism. Current Opinion inNeurobiology, 7, 708-712.

Rapin, L. & Katzman, R. (1998). Neurobiology of autism. Ann Neurology,43, 7-14.

Similar to autistic spectrum disorder, many other behavioral,neurological and immunological disorders have been equally difficult tounderstand and to effectively treat. Such disorders include depression,obsessive-compulsive disorder, Alzheimer's, allergies, anorexia,schizophrenia, as well as other neurological conditions resulting fromimproper modulation of neurotransmitter levels or improper modulation ofimmune system functions, as well as behavioral disorders such as ADD(Attention Deficit Disorder) and ADHD (Attention Deficit HyperactivityDisorder), for example. Accordingly, a need exists for a method andcomposition for the treatment of autism and other behavioral,neurological and/or immunological disorders.

The hormone secretin is a polypeptide hormone secreted by the mucosa ofthe duodenum and upper jejunum when acid chyme enters the intestine. Thehormone secretin stimulates the pancreatic acinar cells to releasebicarbonate and water, which are excreted into the duodenum and changethe pH in the gut from acid to alkaline, thereby facilitating the actionof digestive enzymes. Secretin is always used and indeed is intendedonly to be used in diagnostic tests given to patients withgastrointestinal disorders to stimulate the release of pancreatic juicesfor testing purposes.

Prior to the discorvery of the present invention however secretin hasnever before been linked to autistic spectrum disorders, either as apossible cause or treatment, nor has it been used in the treatment ofother neurological and/or

Wing, L. (1997). The autistic spectrum. The Lancet, 350 (December 13),1761-1765. immunological disorders, as herein proposed.

SUMMARY OF THE INVENTION

The present invention features a method for the treatment ofneurological, immunological and other disorders in a patient. The methodcomprises the step of stimulating the secretion of pancreatic juices inthe patient. In one embodiment, stimulating the secretion of pancreaticjuices comprises the step of administering to the patient an effectiveamount of natural or synthetic secretin. The preferred method of thepresent invention is for the treatment of autistic spectrum disorder.

According to one method of administering secretin, the secretin isadministered by infusion and the effective amount is generally 2clinical units (CU) per kilogram (kg) of body weight given intravenouslywithin 1 minute. In another method, the secretin is administeredtransdermally by applying a transdermal carrier substance, such asdimethyl sulfoxide (DMSO) to the skin, applying crystalline secretin inan effective amount onto the carrier substance, and rubbing thecomposition into the skin. One example of an effective amount ofsecretin administered transdermally includes about 15 CU of crystallinesecretin.

Other methods of administering secretin include, but are not limited to,administering secretin transdermally with a gel, lotion or patch;administering secretin with a suppository; administrating secretinorally, as tablet, capsule or lozenge; administrating secretin byinhalation (e.g., as an aerosol) either through the mouth or the nose;and administering secretin using acoustic waves to permeate the skin.The present invention also contemplates other physiologically acceptablecarriers or excipients for carrying an effective amount of secretin intothe patient's body.

In another embodiment, the method for stimulating the secretion ofpancreatic juices comprises the step of causing the body to secretesecretin in an effective amount to at least ameliorate and preferablytreat autism and other neurological and/or immunological disorders. Thismethod includes, for example, stimulating or otherwise causing theduodenum and upper jejunum to secrete the hormone secretin for one ormore of the purposes described herein.

The present invention also features compositions for use according tothe above methods. In one embodiment, a pharmaceutical composition,according to the present invention includes an effective amount ofsecretin together with a suitable volume of sodium chloride fordissolving the secretin and carrying the secretin into the body byinfusion. In another embodiment, a composition according to the presentinvention includes an effective amount of secretin and a transdermalcarrier substance, such as DMSO for carrying the secretin into the bodytransdermally. Other compositions include an effective amount ofsecretin together with physiologically acceptable carriers or excipientsfor carrying the secretin into the patient's body. The present inventioncontemplates the use of both natural and synthetically producedsecretin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will be better understood from the followingexamples which are given by way of illustration and not by way oflimitation. The patient, the same in both examples, is a boy withsymptoms of autism. Although only two examples of treatment arepresented on the same patient, the present invention has been tried on anumber of children in accordance with the method of the first examplewith similar satisfactory results.

The patient in the present examples developed normally until aboutfourteen months of age, with the exception of gastrointestinal problems(i.e., chronic diarrhea and constipation) which began at about sixmonths. At about thirteen months, when whole milk was introduced intohis diet, the patient began having reoccurring ear infections. At aboutfourteen months, the patient appeared to lose the ability to processlanguage, first receptively (at about 14 months) then expressively (atabout 16 months). The patient also experienced episodes of “shivers”that appeared to be intermittent seizures.

After consulting with numerous neurologists, pediatricians, childdevelopment specialists, audiologists, endocrinologists, allergists, andother medical professionals, no consistent diagnosis had been reached.Although not clinically diagnosed with autism, the patient exhibits anumber of behavioral symptoms of autism and pervasive developmentaldisorder (PDD) in general. The term autism is used herein for referencepurposes only, and this invention is intended to apply to any number ofpervasive developmental disorders as well as neurological andimmunological disorders.

Prior to receiving the treatment with secretin, a single photon emissioncomputed tomography (SPECT) scan of the brain revealed a decreasedperfusion in the right hemisphere and left temporal lobe, with the mostsevere decrease in the right parietal occipital region. Also, steadystate auditory evoked responses recorded in response to rapid amplitudeand frequency modulations of a 1 kHz tone were abnormal, suggestingdisturbances of neural mechanisms responsible for frequency andamplitude modulation analysis. Further, the patient's secretin cellsprior to receiving treatment, measured at a level of 9, are far belowthe normal limit in the range of 20-70.

EXAMPLE 1

When the patient was three years old, the secretin was administered byway of an infusion as part of an upper gastrointestinal endoscopy. Thesecretin was used in this diagnostic procedure at the request of thepatient's parents, one of which is an inventor of the present invention.The secretin used in this procedure is known as Secretin-Ferringavailable from Ferring Laboratories, Inc., Suffern, N.Y. (See AppendixA). The secretin was dissolved in a 7.5 solution of sodium chloride andadministered in a dosage of 2 clinical units (CU) per kilogram (kg) bodyweight by intravenous injection over one minute. (I.E. 30 IU IV forapproximately 15 kilograms of body weight.)

Immediately after the administration of the secretin, the diagnostictesting revealed that the patient's pancreas responded, quitesurprisingly, with an unusually large amount of pancreatic juice beingreleased (approximately 10 ml/min compared to a usual rate of 1-2ml/min). The diagnostic tests performed on the patient during thisprocedure also indicated gastric inflammation. Within days after theadministration of secretin, the patient's chronic abnormal bowelmovements became normal, although no changes had been made in thepatient's diet. Within weeks after the treatment, the patient was ableto make normal eye contact, language appeared for the first time in twoyears, and other behavioral and developmental problems improvedremarkably. The following Table I summarizes the improvements observedin the patient within 3 weeks after the infusion of secretin.

TABLE I Symptoms Before Secretin Progress within 3 Weeks Infusion Afterthe Secretin Infusion Two words 100's of words - will repeat someapproximation of any work requested. No sentences Short sentences - suchas; “I love you”, “I want juice”, “Good night mommy”, “Thank you,daddy”. No flash cards 40-50 flash cards. No focus on requested tasksWill sit and watch carefully. Will perform most tasks after watchingonce or twice. For instance, will sort by color or category. Willconstruct more complicated puzzles. Will respond appropriately toquestions. Diapers only Completely potty trained. Watch Videos Now, gets“involved” interactively with his videos. He will imitate the handmotions, sing the songs or dance to the music. Consistent sleepingproblems. Has slept through almost every night Although these were muchentirely. worse when he was 18-24 months, prior to the procedure he wasstill up numerous times each night. Infrequent (1-2 times/week) Nospinning episodes. “spinning” episodes. Abnormal bowel movements Normalbowel movements. Excessive water consumption Excessive waterconsumption - no approximately 50 cups per day. change approximately 50cups per day. Limited Diet Preferences No Change (French Toast, bananas,French Fries, pancakes, crackers, cookies, raisins, chocolate, chickennuggets.) No apparent connections made Many connections made betweenbetween language and objects. new language learned and objects. Recitesnames he has learned on flash cards when he sees the same on computergame or video. No response to request for Responds to all kinds ofthings gestures. such as, “blow a kiss”, “Wave bye bye”, etc. Will oftennow spon- taneously say these things himself. No interest in drawingWants to draw constantly. Will draw complete face and name the parts ashe draws. Did not imitate commands. Will imitate almost any multi-stepcommand. Minimal eye contact Eye contact 75% of the time.

Biomedical changes were also measured in the patient. A SPECT scan ofthe patient indicated that the perfusion of the right posterior parietaland right temporal lobes was improved. Blood tests taken after thetreatment also indicated a rise in serotonin levels, and the patient'srubella titers dropped from 5.8 to 2.3.

Although the behavioral improvements continued, the rate of thepatient's progress appeared to decrease at about 5 weeks. At the requestof the patient's parents, a second infusion of secretin was performedabout 9 months after the first infusion, and a third infusion ofsecretin was performed about three months after the second infusion. Thesecond and third infusions of secretin achieved the same results in thepatient.

EXAMPLE 2

At the time of this treatment, the patient was about 4 years old.Secretin was administered transdermally using pharmaceutical gradedimethyl sulfoxide (DMSO) (generally 99.9% pure) available from ClinicService Co., Box 2512, Hemet Calif. 92543. The secretin(Secretin-Ferring) was administered daily in a dosage of about 75 CUover a five day period (i.e., about 15 CU daily). For each treatment,about 4 drops of DMSO were placed onto the skin of the patient, about 15CU of the crystalline secretin was placed onto the DMSO, and thecomposition was rubbed into the skin.

The administration of secretin transdermally on a daily basis in thisway has resulted in even more dramatic and significant improvements inthe patient. Within a period of about 6 months, the patient hasprogressed to spontaneous and conversational language. When the dailydose of secretin is stopped, the autistic behavioral symptoms return.

It is important to note that similar results have been seen in numerousother autistic children using an intravenous administration of secretinin accordance with the teachings of the present invention, in order tovalidate the findings of the present invention.

Although the present invention is not limited by theory, it is believedthat some autistic spectrum disorders are caused by a secretindeficiency resulting in a dysfunction of the pancreas. One function ofthe hormone secretin is to stimulate the pancreas to release bicarbonateand water, which change the pH in the gut from acid to alkaline, therebyfacilitating the action of digestive enzymes. The gastrointestinaldisorders, such as an inability to digest gluten and casein, in autisticpatients is possibly caused by this failure of the pancreas to releaseenzymes.

One possibility is that abnormal opioid peptides in the gut createproblems in the brain. These abnormal opioid peptides have been found todiminish on a casein free and gluten free diet. According to one study,autistic children that responded to this diet were given an infusion ofsecretin and the peptides were measured before and after the secretininfusion. After the secretin infusion, which stimulates the pancreas torelease bicarbonate, the peptides disappeared.

The gastric inflammation observed in the patient in the above EXAMPLE 1suggests that the improper pH resulting from this dysfunction of thepancreas may be a cause of the digestive problems and malabsorption ofessential minerals and nutrients found in many individuals with autism.The unusual secretion by the pancreas in response to the secretin, asobserved in EXAMPLE 1, further suggests that this dysfunction of thepancreas is caused by a secretin deficiency.

In addition to this effect on the digestive function, secretin alsoappears to improve the abnormal brain activity in individuals havingsymptoms of autism. The increased blood flow in the brain detectedduring a SPECT scan after administering secretin in EXAMPLE 1 supportsthis theory. While causing pancreatic secretions, secretin alsostimulates the production of cholecystokinin (CCK). Deficiencies in CCKhave been linked to other neurological disorders, such as schizophrenia,and CCK production has been found to be related to levels of theneurotransmitter serotonin. Thus, secretin may be indirectly related tothe body's natural production of serotonin. The increase in serotoninlevels in the blood after the procedure in EXAMPLE 1 supports thisrelationship between secretin and serotonin.

Without proper modulation of neurotransmitter levels (i.e., serotonin)in the brain, the brain will not function properly. The inability tomodulate neurotransmitter levels has been found to be related to otherneurological conditions as well as autism. Thus, a secretin deficiencymay cause an imbalance or improper modulation of neurotransmitter levelsthat results in autistic spectrum disorder or other neurologicaldisorders. Administering secretin to patients with these disorders willmodulate the neurotransmitter levels and correct the behavioralsymptoms, such as the inability to process language and othermaladaptive behavioral patterns. The secretin may also correctabnormalities in immune system functions, as indicated by the reductionof measles, mumps and rubella antibodies in the patient after thesecretin administration in EXAMPLE 1. Secretin has also been found tostimulate dopamine production through its precursor, tyrosinehydroxylase. Dopamine levels have been implicated in a variety of mentaland behavioral disorders such as Parkinson's and Alzheimer's disease.

A secretin deficiency can therefore account for the gastrointestinaldisorders as well as the behavioral symptoms found in many individualswith autistic spectrum disorder.

The therapeutic possibilities of the use of secretin appear to have beenoverlooked in the medical literature. For example, Guyton and Hall, intheir widely used Textbook of Medical Physiolocy (9th edition,1995-1997) mention briefly in passing that secretin can increasecellular utilization of insulin. Recent research suggests that insulinis required for normal brain functioning. (See also Science vol. 280Apr. 24, 1998, p. 517-518). Furthermore, immunological disorders relatedto abnormally high levels of measles, mumps, and rubella (MMR) titersmay also be treatable with secretin. Additionally, secretin is believedto stimulate antibodies to cows milk protein (and perhaps otherproteins). Autism and other PDD's may be connected to proteinintolerance and secretin may increase the body's tolerance to suchprotein(s). Secretin may also have histamine blocking capabilities.

Although the above examples use Secretin-Ferring, the present inventioncontemplates other forms of natural or synthetic secretin. The presentinvention also contemplates using other types of transdermal carriersubstances in addition to DMSO. Further, the present inventioncontemplates other alternative ways of administering secretin including,but not limited to, administering secretin transdermally with a gel,lotion or patch; administering secretin with a suppository;administrating secretin orally, as tablet, capsule or lozenge;administrating secretin by inhalation (e.g., as an aerosol) eitherthrough the mouth or the nose. Such alternative methods of administeringsecretin are less invasive, do not have to be carried out by a doctor ata medical facility, and are less expensive. In addition, the level ordose of administration of secretin can be varied from those examplesstated herein including, for example, intraveneous administration over aperiod of time of several hours instead of several minutes and/or asmaller, maintenance or daily dose administered intramuscularly,transdermally or by other methods as disclosed herein or theirequivalent.

A further alternative method of transdermally administering secretinincludes the use of acoustic waves to permeate the skin. For example,acoustic waves generated using ultrasound or a shockwave from a pulsedlaser have been found to make the skin temporarily permeable. A fewminutes of low-frequency ultrasound (sound greater in frequency than 20kilohertz) creates tiny cavities through which the secretin (alone orcombined with another transdermal carrier substance) can be diffused.

Accordingly, the method of treating autism by administering secretinand/or causing the body to naturally secrete required amounts ofsecretin corrects the secretin deficiency, improving the digestivefunctions in autistic patients previously experiencing intestinaldifficulties and improving communication, cognition, and socializationcapabilities of autistic patients. Since other neurological disorders,such as depression, obsessive-compulsive disorder, Alzheimer's,allergies, anorexia, bulimia, schizophrenia, also involve abnormalmodulation of neurotransmitter levels, these disorders may also betreatable with secretin. Further, other disorders related to serotoninand dopamine may also be treatable with secretin.

Modifications and substitutions by one of ordinary skill in the art areconsidered to be within the scope of the present invention which is notto be limited except by the claims which follow.

What is claimed is:
 1. A method for treating a patient exhibiting asymptom of autistic disorder comprising the step of stimulatingsecretion of pancreatic juices in said patient.
 2. The method of claim 1wherein the step of stimulating secretion of pancreatic juices comprisesthe step of administering to said patient an amount of secretineffective to stimulate secretion of the pancreatic juices.
 3. The methodof claim 2 wherein said effective amount of secretin is administered byinfusion.
 4. The method of claim 3 wherein administering said effectiveamount of secretin by infusion includes the step of intravenouslyinfusing secretin in an amount of about 2 clinical units (CU) perkilogram (kg) of body weight.
 5. The method of claim 4 wherein saideffective amount of secretin is administered transdermally.
 6. Themethod of claim 5 wherein administering said effective amount ofsecretin transdermally includes the steps of: applying a transdermalcarrier to a portion of the skin of said patient; and applyingcrystalline secretin in said effective amount onto said transdermalcarrier.
 7. The method of claim 6 wherein said transdermal carrierincludes dimethyl sulfoxide (DMSO).
 8. The method of claim 6 whereinsaid effective amount of secretin includes between 5 and 20 clinicalunits (CU) of crystalline secretin per dose.
 9. The method of claim 6wherein said transdermal carrier is selected from the group consistingof a gel and a lotion.
 10. The method of claim 5 wherein administeringsecretin transdermally includes administering said effective amount ofsecretin with a patch to be applied to a portion of the skin of saidpatient.
 11. The method of claim 2 wherein said effective amount ofsecretin is administered orally.
 12. The method of claim 11 wherein saideffective amount of secretin is administered orally using an oralcarrier selected from the group consisting of a tablet, capsule orlozenge.
 13. The method of claim 2 wherein said effective amount ofsecretin is administered using a suppository.
 14. The method of claim 2wherein said effective amount of secretin is administered by inhalation.15. The method of claim 2 wherein said patient suffers from autisticdisorder or pervasive development disorder.
 16. The method of claim 2wherein said effective amount of secretin includes an amount of secretinsufficient to increase serotonin levels in the brain of said patient toa level effective to stimulate secretion of the pancreatic juices. 17.The method of claim 1 wherein stimulating secretion of said pancreaticjuices increases at least one neuropeptide hormone selected from thegroup consisting of serotonin, dopamine and CCK levels in said patient.18. A method for the treatment of autism comprising the step ofadministering to said patient an effective amount of secretin.
 19. Themethod of claim 18 wherein said effective amount of secretin isadministered by infusion.
 20. The method of claim 19 whereinadministering said effective amount of secretin by infusion includes thestep of intravenously transfusing secretin in an amount of about 2clinical units (CU) per kilogram (kg) of body weight per dose.
 21. Themethod 18 wherein said effective amount of secretin is administeredtransdermally.
 22. The method of claim 21 wherein administering saideffective amount of secretin transdermally includes the steps ofapplying a transdermal carrier to a portion of the skin of said patient;and applying crystalline secretin in said effective amount onto saidtransdermal carrier.
 23. The method of claim 22 wherein said transdermalcarrier includes dimethyl sulfoxide (DMSO).
 24. The method of claim 23wherein said effective amount of secretin includes about 15 clinicalunits (CU) of crystalline secretin per dose.